1. Description of the problem

As psychiatric illness becomes better recognized and treated, the number of prescriptions for psychiatric medications has substantially increased. Psychiatric medications can be divided into several general categories, including the antipsychotics, antidepressants, and mood stabilizers. Many anticonvulsants are also used as mood stabilizers; these are discussed separately, as is lithium.

The two major classes of psychiatric medications that will be discussed in this chapter are the antipsychotics and antidepressants. The word "antipsychotics" is somewhat of a misnomer, however, as these drugs are used in the treatment of many conditions besides simply acute psychosis. For example, many of the atypical antipsychotics are often used in the management of insomnia.

Clinical features

Antidepressants

The features of an antidepressant overdose depend on the type of antidepressant.

In general, overdose of the selective serotonin reuptake inhibitors (SSRIs) is well tolerated and frequently results in no symptoms. Occasionally, some gastrointestinal symptoms, such as nausea and vomiting, can occur. Seizures can occur but are relatively rare. Serotonin syndrome has clearly been described following isolated SSRI overdose but nonetheless remains relatively uncommon following isolated SSRI overdose. Serotonin syndrome is much more common when an SSRI is taken with a different xenobiotic, which also increases the concentration of serotonin in the synaptic cleft.

Features of serotonin syndrome include altered mental status, diaphoresis, diarrhea, autonomic instability, and rigidity. Tachycardia and hypertension are more common in serotonin syndrome than is hypotension. The rigidity of serotonin syndrome classically involves the lower extremities much more so than the upper extremities. Inducible or spontaneous clonus of the lower extremities is very common with serotonin syndrome. Prolongation of the QT interval can be observed following SSRI overdose, especially in cases involving citalopram or escitalopram.

Overdose of the selective norepinephrine-serotonin reuptake inhibitors (SNRIs) can result in CNS depression, seizures, and tachycardia. Rarely, acute cardiomyopathy or serotonin syndrome has been described following overdose of these medications. Venlafaxine is associated with QRS prolongation in overdose, and can result in ventricular dysrhythmias.

Overdose of the tricyclic antidepressants (TCAs) typically produces symptoms within the first 2 hours of ingestion, and nearly always within the first 6 hours of an ingestion. The symptoms of a TCA overdose include CNS depression, hypotension, seizures, and anticholinergic toxicity. Orthostasis is quite common. Sodium channel blockade produces intraventricular conduction delay, manifesting as QRS prolongation, while potassium efflux blockade can produce QT prolongation.

Patients who overdose on monoamine oxidase inhibitors (MAOIs) are classically asymptomatic for many hours post ingestion. Thus, all intentional ingestions of MAOIs (especially those involving inhibition of MAO-A) require admission to an intensive care unit despite an early period of being asymptomatic. Twelve to 24 hours post ingestion, tachycardia and hypertension are common, followed by cardiovascular collapse with hypotension and bradycardia, CNS depression, and possibly seizures. Serotonin syndrome is associated with MAOIs.

Antipsychotics

Antipsychotics have historically been divided into the typical and atypical antipsychotics. Because of the adverse effects associated with the typical agents, including the high rate of extrapyramidal symptoms at clinically effective antipsychotic doses, their ability to produce tardive dyskinesia, and their relative ineffectiveness at treating the negative symptoms of schizophrenia, the atypical agents have become more widely used in recent years.

As a general rule, the typical agents (e.g., haloperidol, droperidol, chlorpromazine, promethazine, prochlorperazine, thioridazine, etc.) have high affinity for the D2 receptor. As a class, the atypical agents (e.g., clozapine, loxapine, quetiapine, olanzapine, risperidone, ziprazidone, aripiprazole, etc.) have less affinity at the dopamine receptors and higher affinity at the serotonin receptors.

In general, the symptoms observed in overdose are exaggerations of the adverse effects seen at therapeutic doses. Each of the drugs has somewhat different binding affinities to various receptors. It is the affinities for these different receptors that predict the adverse effects observed in overdose.

CNS depression is quite common with many of these drugs, and in part, relates to their antagonism of the H1 histamine receptor. Anticholinergic effects are observed with some of the typical antipsychotics (e.g., chlorpromazine, loxapine, mesoridazine, and thioridazine) and are quite common with many of the atypical antipsychotics (e.g., clozapine, olanzapine, quetiapine). This anticholinergic toxicity includes altered mental status, urinary retention, tachycardia, dry mucosal membranes, and hyperpyrexia. Of note, due to competing effects of the alpha receptors, the mydriatic pupils that are classically observed with anticholinergic toxicity is often absent in cases of anticholinergic toxicity due to antipsychotics. Despite the classic dry mucosal membranes with most anticholinergic drugs, patients who overdose on clozapine frequently present with sialorrhea.

Hypotension is common, and is largely related to orthostasis. However, some hypotension can be observed due to direct myocardial depression. Orthostasis is quite common with many of these agents, and relates to the antagonism of the alpha receptors. While the vasodilation may not be quite apparent in a patient with minimal symptoms, it can be quite impressive with positional changes. It is because of this orthostasis that all patients with antipsychotic overdoses must be ambulated prior to medical clearance. Due to potassium efflux blockade, QT prolongation is quite common. However, because these patients are usually also tachycardic, torsades is quite uncommon.

All antipsychotics can lower the seizure threshold. Nonetheless, overall, seizures are relatively rare. While some antipsychotics (clozapine, loxapine, and some of the phenothiazines) have a higher propensity to cause seizures, seizures remain relatively rare even with these medications.

Extrapyramidal effects are well described with all antipsychotics, especially the typical antipsychotics. These extrapyramidal symptoms can be divided into reversible syndromes (acute dystonia, akathisia, parkinsonism, neuroleptic malignant syndrome [NMS]) and irreversible syndromes (tardive dyskinesia or focal perioral tremor). In general, the timing for these symptoms differs depending on the symptom. Acute dystonia or akathisia generally occurs within hours to days of starting the medication, while tardive dyskinesia generally occurs after months to years of being on a medication. Akathisia can be described as a subjective sense of unease and motor restlessness. It can be misinterpreted as increasing agitation or anxiety. Acute dystonia is a hyperkinetic movement disorder that manifests as intermittent or sustained muscle contractions. The common clinical manifestations of acute dystonia include trismus, torticollis, facial grimacing, opisthotonus, and oculogyric crisis. Rarely, pharyngeal or laryngeal muscle spasm can occur, which can interfere with respiration.

Neuroleptic malignant syndrome is an uncommon but potential complication of antipsychotic use. It is an idiosyncratic reaction that frequently begins early in the course of therapy or following an increase in the daily dosage. The symptoms generally have an onset over 1-3 days and are characterized by altered mental status, muscular rigidity, and autonomic dysfunction. Alterations in mental status and muscular rigidity generally occur prior to autonomic instability. The muscular rigidity is described as a "lead pipe" rigidity, and is associated with "cogwheeling." Rhabdomyolysis, leukocytosis, and renal failure can occur.

Key management points

Antidepressant

The primary treatment of antidepressant overdose is supportive. With any of the antidepressants, CNS depression may require endotracheal intubation.

Patients with isolated SSRI overdoses frequently do not require any specific therapy and can be cleared from the emergency department. Isolated seizures should be treated with benzodiazepines. Serotonin syndrome (which is more common with mixed overdoses rather than isolated SSRI overdoses) should be treated with aggressive benzodiazepines. Cyproheptadine can be given as an adjunctive therapy along with benzodiazepines, but benzodiazepines and aggressive supportive care are the cornerstone of therapy for serotonin syndrome.

Hypotension from a TCA overdose should first be treated with intravenous crystalloid fluid resuscitation. If hypotension persists after an appropriate amount of crystalloids, direct-acting vasopressors, such as levophed or epinephrine infusions, should be started. Seizures should be treated with sodium bicarbonate boluses as well as benzodiazepines. Intraventricular conduction delay should be treated with sodium bicarbonate boluses. Bicarbonate infusions (e.g., 1 L of D5W with 150 mEq of sodium bicarbonate, with or without supplemental potassium) can be infused at a rate of 1-2 times maintenance, but should be performed only after boluses of sodium bicarbonate. The goal arterial pH is 7.50-7.55.

Care should be taken not to excede 7.55. If intraventricular conduction delay persists after aggressive alkalinization, hypertonic saline (e.g., 100 cc of 3% for an adult) can be administered. Intravenous lipid infusion can be used, but due to the relative novelty of this drug and the potential for complications, its use should be reserved for patients with profound hemodynamic instability or dysrhythmias that persist despite appropriate amounts of sodium bicarbonate.

Patients who present with an MAOI ingestion are usually asymptomatic early. Any early hypertension should ideally not be treated unless severe. If profound hypertension occurs, it should be treated with a short-acting agent, such as nipride or esmolol. Hypotension should be treated with IV fluid boluses, followed quickly by infusion of a direct-acting vasopressor, such as levophed or epinephrine. Because the hypotension in MAOI overdose results from depletion of presynaptic catecholamines, use of indirect-acting vasopressors, such as dopamine, is unlikely to be beneficial.

Antipsychotic

The primary therapy for antipsychotic overdose is supportive. Patients with CNS depression or respiratory insufficiency may need to be intubated. Those patients with a QT interval greater than 500 msec should receive 2-4 grams of magnesium sulfate, assuming no contraindications to its use exist. Seizures should be treated with benzodiazepines initially, although refractory seizures should be treated with barbiturates such as phenobarbital.

2. Emergency Management

The first step in the management of any poisoned patient is ensuring the patient has an adequate and patent airway. If the patient is not adequately protecting the airway, or if there is concern that the patient is rapidly becoming more somnolent and will lose the ability to protect the airway, endotracheal intubation should be performed. After you ensure that an adequate airway exists, breathing should be monitored and respiratory distress should be treated. Hypotension should be treated initially with crystalloids, with vasopressors being used second.

Any patient with an altered mental status should have a capillary glucose determined.

Subsequent treatment depends on the specifics of the agent ingested and laboratory and physical examination findings (e.g., benzodiazepines for seizures, sodium bicarbonate for intraventricular conduction delay, etc.). All patients with a known or suspected overdose should undergo an electrocardiogram and should be observed closely in a monitored setting.

Management points not to be missed

Supportive care is paramount to patients with antidepressant or antipsychotic overdose.

Close attention must be focused on the 12-lead electrocardiogram, with particular attention to the QRS and QT intervals.

Hyperthermia due to increased neuromuscular excitability needs aggressive benzodiazepines, and possibly neuromuscular blockade with use of a non-depolarizing paralytic.

3. Diagnosis

Diagnostic tests

All patients with a suspected overdose need to have a 12-lead electrocardiogram performed. Basic chemistry tests, including electrolytes and glucose, should be determined on all overdose patients. Serum acetaminophen and salicylate concentrations should be obtained to exclude mixed ingestions. Patients with increased agitation need to have the CK monitored to assess for rhabdomyolysis.

Diagnostic approach

History is the essential in determining the etiology of the symptoms. Certainly aggressive supportive care is key, and patient care should not be delayed while trying to obtain a history. Frequently, the constellation of symptoms can be a diagnostic clue as to the class of agent a patient might have taken (e.g., anticholinergic features with QT prolongation in a patient with a history of psychosis can suggest antipsychotic overdose), although clearly many other agents can produce similar symptoms. Thus, the history and exam can suggest a class of drugs but will not be able to distinguish the exact agent involved.

Differential diagnosis

The differential diagnosis depends on the exact signs and symptoms the patient is exhibiting. Certainly seizures from any etiology, hypoglycemia, thyroid storm, head injury, and CNS infection can all present with many similar features to overdose on these agents.

Confirmatory tests

No specific confirmatory test is indicated. The value of a basic urine drug screen (e.g., one performed by immunoassay) cannot confirm or exclude an overdose.

4. Specific Treatment

The primary treatment is supportive.

Patients with altered mental status and poor airway control should be intubated.

A capillary glucose should be determined on anyone with altered mental status, with dextrose given if hypoglycemia is present.

Seizures should be treated initially with benzodiazepines, with barbiturates reserved for refractory seizures.

Sodium bicarbonate should be given for drug-induced QRS prolongation. Hyertonic saline can be used for QRS prolongation refractory to adequate serum alkalinization.

Urinary alkalinization may be necessary for rhabdomyolysis.

Optimal management of any particular overdose is best treated on a case-by-case basis, and should be discussed with a medical toxicologist or poison control (800 222-1222).

Drugs and dosages

Seizures should be treated with benzodiazepines. Any benzodiazepine is acceptable, but some commonly used benzodiazepines include lorazepam (1-2 mg IV q 3-5 minutes for seizures) or diazepam (5-10 mg IV q 10 minutes).

Sodium bicarbonate (100-150 mEq) should be administered as an IV bolus for drug-induced QRS prolongation. This dose can be repeated for treatment of drug-induced QRS prolongation until there is normalizing of the QRS, or until an arterial pH of 7.5-7.55 is achieved. A continuous infusion of 1 L of D5W with 150 mEq sodium bicarbonate (with or without potassium) can be started as an adjunctive therapy for drug-induced QRS prolongation, but should not be considered a substitute for the IV boluses. If an infusion is started, it should be run at 1.5-2 times maintenance.

Cyproheptadine can be given for serotonin syndrome but should be considered as an adjunctive therapy to benzodiazepines. It should be given at 8-12 mg orally a single time, and can be redosed at 2 mg every 4 hours for 2-3 doses. Cyproheptadine is itself anticholinergic and should not be given if coexisting anticholinergic toxicity is present.

Refractory cases

Hypertonic saline can be given for drug-induced QRS therapy that is not improving or worsening despite an arterial pH of 7.55.

5. Disease monitoring, follow-up and disposition

Expected response to treatment

The primary treatment is supportive.

The primary potential complications include aspiration and rhabdomyolysis. These topics are discussed separately. Ventricular dysrhythmias are infrequent, but if treated appropriately usually respond to appropriate treatment.

Incorrect diagnosis

If the patient fails to improve, one should consider another drug/toxin, or another diagnosis.

Follow-up

Patients should receive psychiatric evaluation.

Pathophysiology

Antidepressants

Antidepressants work by different mechanisms, but ultimately most attempt to correct an imbalance of the dopaminergic, noradrenergic, and serotonergic systems.

MAO-I

Monoamine oxidase is an enzyme located on the outer mitochondrial membrane. It functions to degrade cytoplasmic catecholamines. The first-generation MAO-Is are nonselective and irreversible, while newer selective MAO-B inhibitors disproportionately increase dopamine concentrations in the striatum. An example of an MAO-B inhibitor is selegiline.

TCA

Tricyclic antidepressants are drugs whose therapeutic effect results from inhibition of monoamine reuptake. However, the adverse effects are due to antagonism of the M1, H1, alpha 1, and alpha 2 receptors. In addition, there is significant inhibition of the sodium channels as well as the potassium efflux channels.

SSRI

Selective serotonin reuptake inhibitors are drugs that interfere with the reuptake of serotonin. As a result of decreased presynaptic reuptake, serotonin accumulates in the synaptic cleft.

SNRI

The SNRIs, such as duloxetine, venlafaxine, desvenlafaxine, and milnacipran, inhibit sodium reuptake as well as other neurotransmitters, such as dopamine or norepinephrine.

Antipsychotics

The typical antipsychotics achieve their therapeutic benefit from antagonism of the D2 receptors. This same antagonism of the D2 receptors that results in therapeutic benefit also is responsible for many of the adverse effects associated with these medications as a result of D2 receptor antagonism in other locations throughout the brain. The atypical antipsychotics have more effect on the serotonin receptors than the dopamine receptors.

Epidemiology

As the prevalence of psychiatric disorders increases in Western society, there is a corresponding increase in the number of prescriptions written for these medications. Overdose of psychiatric medications is quite common. Collectively, sedative-hypnotic agents, antipsychotics, and antidepressants account for nearly 10% of all calls to US Poison Control Centers.

Prognosis

In general, patients who arrive alive at health care facilities have a very good prognosis. Most deaths from these agents occur in the prehospital period. Thus, if an individual survives to hospital admission, the prognosis is quite good.